Amide derivatives having antiatherosclerosis action

ABSTRACT

WHEREIN R1, R2, R3 and R4 are as defined above.   WHEREIN R represents a C15-C25, straight chain or branchedchain, natural or synthetic, saturated or unsaturated aliphatic group having or not having hydroxyl group; R1, R2, R3 and R4 represent individually a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom but cannot be hydrogen atoms at the same time. The above-mentioned amide compounds can be used as drugs. They can be used by adding them to food-stuff additives such as butter and the like for prventing the deposition of cholesterol onto the walls of blood vessels. The amide compounds are prepared by reacting fatty acids, reactive derivatives thereof, fatty acid halides, fatty acid anhydrides, fatty acid esters or glycerides with racemic, d- or l-amines represented by the formula   Amide compounds having antiatherosclerosis actions which are represented by the formula;

United States Patent [191 111 3,764,704 Nakamura et a]. Oct. 9, 1973 4] AMIDE DERIVATIVES HAVING ANTIATHEROSCLEROSIS ACTION RGONHCH [75] Inventors: Yasushi Nakamura, Ibaragi; Michio Kimura, Minoo; Yoshio Suzuki, -4 g Amagasaki; Noritaka Hamma, ,,Vi m b a. a Nishinomiya; Toshitsugu Fukumaru, Kyotoi'shunll Afmoi PYQ wherein R represents a C -C straight chain or Hldeakl Fllkllshlma, Nlshlnomlya, branched-chain, natural or synthetic, saturated or unlQflPRQQ. w saturated aliphatic group having or not having hy- [73] Assignee: Sumitomo Chemical Company, Ltd., droxyl group; R3 and R4 represent individually Osaka, Japan a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom but cannot be hydrogen [22] Filed: l"- 1971 atoms at the same time. [21] Appl. No.: 131,768 The above-mentioned amide compounds can be used as drugs. They can be used by adding them to O Related Application food-stuff additives such as butter and the like for [6 N- 1969' prventing the deposition of cholesterol onto the walls No. 3,597,458, which is a continuation-impart of Ser. of blood vessels No. 794,038, Jan. 27, 1969, abandoned.

The amide compounds are prepared by reacting fatty 52 US. Cl. 424/324 acids, reactive derivatives thereof, fatty acid halides, 51 Im. Cl ..A61k 27/00 fatty acid anhydrides, fatty acid esters or glycerides [58] Field of Search 424/320, 324 with racemic, or l-amines represented y the I formula [56] References Cited UNITED STATES PATENTS RPR: 2,503,285 4/1950 McPhee 260/5705 Primary Examiner--Albert T. Meyers Assistant Examiner-Frederick E. Waddell Att0mey-Stevens, Davis, Miller & Mosher [5 7] ABSTRACT Amide compounds having antiatherosclerosis actions which are represented by the formula;

Rs-RI LPG wherein R R R and R are as defined above.

2 Claims, 4 Drawing Figures AMIDE DERIVATIVES HAVING ANTIATHEROSCLEROSIS ACTION Ri-Ra Ra-Ra wherein R represents a C C straight chain or branched-chain, natural or synthetic, saturated or unsaturated aliphatic group having or not having hydroxyl group; R R R and R represent individually a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom but cannot be hydrogen atoms atthe same time.

An object of the present invention is to provide novel amide compounds, which are effective for prevention of hypercholesterolemia and atherosclerosis.

Another object is to provide a process for preparing said novel amide compounds.

A further object is to provide pharmaceutical compositions containing said novel amide compounds as active ingredients.

Fatty acid amide derivatives involved in the present invention have excellent cholesterol-lowering actions and preventing actions of atherosclerosis and, as the result of toxicity tests carried out for the past several years, it has been found that they have no undesirable acute and chronic toxicity.

The present compounds are used at a dosage of 0.1 g-lO g/day for human beings. They are used with or without admixing with suitable carriers. It is preferable to apply in the form of capsule, tablet, powder etc.

In the accompanying drawings, FIGS. 1 to 4 show infrared absorption spectra of several amide compounds obtained in accordance with the present invention.

FIG. 1:

CuHuCONHCH-Qcl (Compound of Example 2) (Compound of Example 14) FIG. 3:

CmlhCONHTH-Q-CH; CHPQ-CH:

(Compound of Example 15) 7 FIG. 4;

mmucoNHTHQcH.

( po nd of E a pl 3.)

The fatty acids and reactive derivatives thereof which are involved in the present invention are saturated fatty acids such as palmitic, stearic, isostearic, arachidic, be-

-henic, lignoceric, pentacosanoic and hexacosanoic acids; and unsaturated fatty acids such as palmitoleic, zoomaric, oleic, petroselinic, elaidic, vaccenic, gadoleic, erucic, brassidic, selacholeic, linoleic, linoelaidic, ricinoleic, eleostearic, linolenic, parinaric, eicosatetraenoic, arachidonic, eicosapentaenoic and docosapentanoic acids. These may be used either individually or in admixture. Fatty acids of the natural oils shown below, preferably liquid acids obtained from the said natural oils, reactive derivatives thereof and glycerides themselves may also be used. The natural oils include hemp-seed oil, linseed oil, perilla oil, oiticica oil, kaya oil, walnut oil, poppy-seed oil, safflower oil, water melon-seed oil, soybean oil, sunflower oil, rice bran oil, pumpkin-seed oil, kaoliang oil, sesame oil, corn oil, rape oil, cottonseed oil, olive oil, cashew oil, tsubaki oil, ergot oil, castor oil, peanut oil, palm oil, palm kernel oil, coconut oil, beef tallow, lard, bone oil, horse fat, locust oil, chrysalis oil, shark oil, cuttlefish oil, sardine oil, mackerel oil, saury oil, herring oil, saurel oil, cod oil, trout oil, grey mullet oil, tunny oil, menuke oil,

menhaden oil, eel oil, flatfish oil, whale'oil, liver oil and residual oil. Further, the reactive derivatives include fatty acid halides, lower alkyl esters of fatty acids, and mixed acid anhydrides thereof with esters of chloroformic acids.

The amines employed in the present invention are benzylbenzylamines in which at least one phenyl group has been substituted by a lower alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-' 503, or Journal of American Chemical Society, Vol.

68, page 1866 (1946).

Further, the above amine may be resolved into optical isomers according to a method described in, for example, Journal fur Praktische Chemie, Vol. 101, page 296 (1921), whereby desired optically active amines can be' obtained in high yields. These optically active amines are also usable for preparation of the present amide derivatives.

The amide derivatives of the present invention are prepared by reacting a fatty acid represented either by the formula RCOA wherein R is as mentioned previously; and A is a hydroxyl group, a lower alkoxy group or a halogen atom, or by the formula RCO mine derivative represented by the general formula i'Ra e- Q Q wherein R R R and R are as mentioned previously.

Modes of practice of the above reaction are explained below.

l. Di-substituted carbodiimide method:

In this method, a di-substituted carbodiimide is used as a dehydrating agent for said acid and amine. As the di-substituted carbodiimide, there may be used diisopropylcarbodiimide, dicyclohexylcarbodiimide, diphenylcarbodiimide or the like. Of these, however, dicyclohexylcarbodiimide is most commonly employed.

According to this method, said fatty acid, disubstituted carbodiimide and amine are individually dissolved in an inert solvent. Subsequently, the three solutions are mixed together under stirring at room temperature or below, and the mixed solution is allowed to stand at room temperature for several hours to several 10 hours, whereby the reaction is complete.

In the above reaction, di-substituted area is formed from said di-substituted carbodiimide. When recovered and dehydrated, the disubstituted urea can be regenerated to, and reused as, the di-substituted carbodiimide. Therefore, it can be said that this method is quite economical.

2. Thermal dehydration method:

According to this method, said fatty acid is charged with an equimolar or excess amount of the amine and the mixture and condensed by dehydration. The reaction mixture is heated at l00-300 C for several hours to several 10 hours. In the above reaction, an acid catalyst such as boric acid may be used if necessary, whereby the reaction time can be shortened in some cases.

3. Catalytic dehydration method:

This method is carried out in the following manner:

The aforesaid fatty acid and amine are dissolved in a suitable solvent. To this solution is added such a dehydrating agent as sulfuric acid, p-phenolsulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid chloride, 65 or an anion or cation exchange resin (e.g. IRA 400, IR 50, IR 120, or Amberlyst 15, 21, 26 or 27). Subsequently, the solution is heated using a waterseparator to remove water formed. Thereafter, the solvent is removed and the resultant is purified, whereby a desired product can be obtained in a markedly high yield and in a simple manner. Alternatively, the object can be achieved by merely heating said acid and amine together with a dehydrating agent in a'tertiary organic amine such as pyridine, picoline or lutidine as the solvent.

V esiiha idqms hsfl;

As the fatty acid halide, any of chlorides, bromides and iodides of the aforesaid fatty acids may be used. Of these, the chloride is the most important fatty acid halide and can be prepared according to an ordinary procedure.

This method is carried out by dissolving or suspending the benzylamine derivative and an alkaline condensing agent in a suitable solvent, and adding drop by drop an fatty acid halides to the said solution or the suspension.

A nqln s ms 9 This method may be carried out in such a manner that a glyceride or lower alkyl ester of fatty acid is mixed with an equimolar amount to about 10 moles of the aforesaid substituted benzylbenzylamine derivativeand the mixture is reacted at an elevated temperature. If necessary, the reaction may be effected in the presence of an inert organic solvent. The reaction time is ordinarily 20-200 hours at below the boiling point of the amine. In order to save the reaction time, however, the reaction is effected in an autoclave to maintain the reaction temperature at above the boiling point of the amine, or methyl, ethyl or propyl alcohol eliminated during the reaction at atmospheric pressure is removed out of the reaction system. Alternatively, a small amount of a basic catalyst is added if necessary to the reaction system, or an alcohol or aqueous solution of the catalyst is added to the reactants, whereby the reaction time may be greatly shortened.

6. Mixed acid anhydride method:

. This method is carried out by reacting at a low temperature the aforesaid substituted benzylbenzylamine derivative with a mixed acid anhydride of chloroformate ester with fatty acid.

It is needless to say that all the amide synthesis methods other than those mentioned above can be utilized in the present invention.

According to the researches of the present inventors, it has been clarified that all the amides obtained by the above methods have excellent biological activities which, in animal tests using mice, rats and rabbits, markedly lower the blood and liver cholesterol thereof, greatly prevent the formation of atheromata on arterial walls, and show no toxicity at all even when administrated for a long period of time. These methods are usable in the case of optical active amines.

Toxicities and biological effects of the present amide derivatives are explained below.

A food high in cholesterol content is given to 10 mice per group. At the same time, 0.05 percent of each of the present amide derivatives is administered to the mice in admixture with said food. When the amounts of serum and liver cholesterol of the mice are measured after 10 days, it is understood that the mice have been greatly lowered in cholesterol. Of many cases tested, several typical cases are shown in the following table:

TABLE 1 L 259 763 fi i Fi inseed oil-C ONH(|JH C e terol, c t r l, (EH2 mg. (mg./ percent) 100 g.) 5 Control (No substance added) 394 2, 840 Linoleic acid 361 3, 225 C H30 208 629 C H CONH-(]JH-C1Ia 00H.

0 Cuttlefish ou-o 0 NH- |:H

224 444 01111310 ONH(l3H- 221 507 Sardine oil-C 0N1I( J1rczm (7H2 230 500 (H3 "Hate ohm-( 3 H- 0 0 H3 (flh Procedures for preparing the present amide deriva- 3O tives are illustrated below with reference to examples.

EXAMPLE 1 V V V i A M i a To a solution of 4 g of a-(p-methoxyphenyD-B- phenylethylamine and 2.7 g of triethylamine in 100 ml l-CnHuCONH-OHQ 200 423 of dry ether was added drop by drop a solution of 5.8 (1H1 g of linoleic acid chloride in 20 ml of dry ether under I stirring over a period of 1.5 hours at 20 C.

The mixed solution was stirred at said temperature for 2 hours and was then allowed to stand overnight at room temperature. Subsequently, the ether solution 1 40 was refluxed for about 2 hours. H, 93g h After completion of the reaction, the ether solution was washed with a 5 percent hydrochloric acid, water, 255 731 a 5 percent sodium carbonate solution and water, in Ci1Ha=00NH 3H- 0H3 this order, and was then dried with anhydrous sodium 0 sulfate. Thereafter, ether was removed by distillation to I obtain 8 g of N-[a-(p-methoxyphenyl)-B-phenylethyl]- linoleamide in the form of colorless paste.

Elementary analysis: 7 v Calculated Found C 80.92 81.05 H 9.69 10.05 N 2.86 3.06 iso-CnHaaC ONHCH- 231 509 1 EXAMPLE 2 CH2 To a solution of 10 g of a-(p-chlorophenyD-B- phenylethylamine and 4.6 g of triethylamine in 150 ml of dry ether was added drop by drop a solution of 13.5 g of linoleic acid chloride in 20 ml of dry ether under 3 mw stirring over a period of 1.5 hours at 20 C.

4 Subsequently, the same operations as in Example 1 Safliower oil-C 0-NH-CH-Q 218 475 were effected to obtain l9 g of N-[a-(p-chlorophenyD- I B-phenylethyl]-lmoleam1de 1n the form of colorless semisolid.

Elementary analysis; Calculated Found c 77.78 77.91 H 8.98 8.88 N 2.83 2.66 CH3 Cl 7% 7.18 6.92

EXAMPLE 3 phenylethyll-linoleamide in the form of colorless semisolid.

Elementary analysis:

Calculated Found EXAMPLE 4 To a mixture of 1.1 g of triethylamine, 50 ml of ether and 4 .g of a-phenyl-B-(p-methoxyphenyl)-ethylamine was added drop by drop 3.3 g of linoleic acid chloride at room temperature over a period of 1 hour. Thereafter, the mixture was stirred for 2 hours and allowed to stand overnight, and then refluxed for 1 hour. The reaction mixture was extracted with ether and the ether. layer was washed with a 5 percent hydrochloric acid, a 5 percent sodium hydroxide solution and water, in this order, and was then dried. Subsequently, the ether was removed by distillation to obtain desired N-[aphenyl-B-(p-methoxyphenyl)-ethyl]-linoleamide in th form of white semisolid.

Elementary analysis:

Calculated Found EXAMPLE 5 Calculated Found EXAMPLE 6 A mixture of 4.7 g of a-(p-ethylphenyD-B- phenylethylamine and 5.8 g of safflower oil was heated under stirring at 180 C for about 70 hours. After completion of the reaction, the reaction mixture was treated in the same manner as in Example 5 to obtain 6.9 g of a desired product in the form of semisolid.

EXAMPLE 7 A mixture of 7 g of a-(p-bromophenyl)-B-(p,mdichlorophenyl)-ethylamine and 5.8 g of methyl ester of olive oil was stirred at 190 C for about 80 hours while excluding methanol distilled out of the reaction system. After completion of the reaction, the reaction mixture was treated according to ordinary procedure to obtain 7.6 g of a desired product in the form of semisolid. I

EXAMPLE 8 A mixture of 2.3 g of a-phenyl-B-(2,5-xylyl)- ethylamine, 2.8 g of isostearic acid and 0.2 g of p-toluenesulfonic acid was boiled for 12 hours in ml of xylene, using a water-separator. The reaction mixture was treated as usual manner to obtain 4.5 g of white semisolid.

Elementary analysis:

Calculated Found C (at 83.03 83.22 H(%) 10.86 10.91 N at 2.85 2.70

EXAMPLE 9 To a mixture of 4 g of a-(p-tolyU-fiphenylethylamine, 4.2 g of dicyclohexylcarbodiimide and 50 ml of toluene was added a mixture of 5.3 g of oleic acid and 50 ml of toluene. The resulting mixture was allowed to stand overnight at room temperature. Subsequently, deposited precipitates were removed by filtration, and excess dicyclohexylcarbodiimide was decomposed by addition of a small amount of acetic acid. Thereafter, the toluene layer was treated as usual manner to obtain 7.9 g of a desired product in the form of semisolid.

Elementary analysis:

. Calculated Found C 83.31 83.52 H (56) 10.38 10.55 N (56) 2.94 2.70

EXAMPLE 10 A mixture of 2.4 g of a-(p-tolyl)-B-(2,5-xylyl)- ethylamine, 2.9 g of methyl isostearate and 0.3 g of sodium methylate was stirred at C for about 10 hours. Subsequently, the reaction mixture was treated according to ordinary procedures to obtain 4.2 g of a desired product in the form of semisolid.

Elementary analysis:

Calculated Found EXAMPLE 11 To a solution of 14 g of linoleic acid and 5.5 g of triethylamine in 100 ml of tetrahydrofuran was added drop by drop 5.9 g of ethyl chloroformate under stirring at -10 C to -5 C. Thereafter, the stirring was further continued at -5 C for 30 minutes, and then a solution of 1 1 g of a-(p-tolyl)-l3-phenylethylamine in 20 ml of tetrahydrofuran was added drop by drop under stirring at 5 C. Thereafter, the temperature was gradually elevated under stirring, and the mixture was stirred at 40 C for additional 30 minutes. Subsequently, the tetrahydrofuran was removed by distillation and the residue was dissolved in ether. The ether solution was treated as usual manner to obtain 21.5 g of white semisolid.

Elementary analysis:

Calculated Found C 84.02 84.31 H (3%) 9.62 9.77 N 3.39 3.20

Other preparation examples of the present amide derivatives are tabulated below.

Halogen, C, percent H, percent N, percent percent EXBm- Physical Calcu- Calcu- Calcu- Calcuple Compound obtamed property lated Found lated Found lated Found latod Found mun" 7 v, Wm W W v .r W .N V. V V V "W..- o i C"HnCONHcH OH2 -.--.do 82.96 83.15 10. 7s m 76 2. 93 a 11 Example Compound obtaincd Physical semisolid Pig-Petty 15 28 Sardine or} 22 Lmseed o1l V V S ern1sohd CONHCHCHIQC:HB

CONHCH-CHw-Q semisolid V r. .F'fifii'iik 23 R 'l I'd I 25 CONHGH-CHQ c oNHcH-cmcm AW W semisolid I 3O Whale oil Semxsohd 24 'l Safflower 0| C CONHCH-CHg-Q-CH.

4O V. -..u,. .v Al

semisolid on. sgswe 9!! semisolid conncn-cm-Q-Om 25 Corn oil CONHCH-CHz-Q-OCIHB W7 i A W m s glisolid r ..o o .v.-.-. 32 i Cod oil semisolid 26 Cuttlefish oil c onncn-cm-Q- CONHCH-Cl-h-Q-CH: Q

semisolid 33 Soybean oil semisolid 27 ckerel oil CONHCH-GHQ 0, percent H, percent N, percent Calcu- Calcu- Calcu- Example Compound obtained Physical property lated Found lated Found lated Found 34 CH3 no 1.5250 83. 77 84. 08 10. 26 10.38 2. 79 2. 81

o nmcwnonQofi l cm C11H;\CONHCH- ]IJCH;

36 M.P., 5051 C 83. 67 83. 59 10. 9.86 2. 96 2. 86

C nmlconnon 37 a p1usl8.0,M.P., 83.67 83.80 10.00 10.23 2.96 2.88

( C11H31CONHCH 80-82 0.

38 (M.P., s1-s3 c.) 83.67 83.77 10.00 9.94 2.96 3.06

CflHnCONHCH (ID-17.8.

I lHr'Q-CH:

39 Semi-solid 84. 02 33. 88 9. 62 9- 49 2- 97 3- 13 Y-CflHflCONHCH CnHaaCONHTH What we claim is: wherein R represents a C C alkyl or alkenyl group A pharmacutlcal comPosmon comprismg which may be substituted by a hydroxyl and R R R antlatheroschlerotically effective amount of an amide and R4 represent individually a hydrogen atom, a lower denvanve of the formula alkyl, a lower alkoxy group or a halogen atom, but can- Rl not be hydrogen atoms at the same time, and a pharm a- R-CO-NHCH ceutically acceptable inert carrier.

2. The composition of claim 1, wherein the amide is Q N-[a-phenyl-B-(p-tolyl)-ethyl]linoleamide. 

2. The composition of claim 1, wherein the amide is N-( Alpha -phenyl- Beta -(p-tolyl)-ethyl)linoleamide. 